chr1-1427608-G-C

Variant names:

• chr1-1427608-G-C
• rs1264284614
• NM_001146685.2:c.313G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001146685.2(TMEM278):​c.313G>C​(p.Ala105Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,186,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A105V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., cov: 14)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: TMEM278 NM_001146685.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

Genes affected

TMEM278 (HGNC:37099): (transmembrane protein 88B) Predicted to enable PDZ domain binding activity. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38355514).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146685.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM278	NM_001146685.2	MANE Select	c.313G>C	p.Ala105Pro	missense	Exon 2 of 2	NP_001140157.1	A6NKF7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM88B	ENST00000378821.4	TSL:2 MANE Select	c.313G>C	p.Ala105Pro	missense	Exon 2 of 2	ENSP00000455099.1	A6NKF7

Frequencies

GnomAD3 genomes AF: 0.0000300 AC: 3 AN: 99898 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.0000400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000440

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000778

GnomAD2 exomes AF: 0.0000162 AC: 1 AN: 61892 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000919

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1087008 Hom.: 0 Cov.: 34 AF XY: 0.00000189 AC XY: 1 AN XY: 528174

African (AFR) AF: 0.00 AC: 0 AN: 21650

American (AMR) AF: 0.0000629 AC: 1 AN: 15906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15606

East Asian (EAS) AF: 0.00 AC: 0 AN: 18220

South Asian (SAS) AF: 0.00 AC: 0 AN: 46888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2880

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 907034

Other (OTH) AF: 0.0000247 AC: 1 AN: 40482

GnomAD4 genome AF: 0.0000300 AC: 3 AN: 99952 Hom.: 0 Cov.: 14 AF XY: 0.0000214 AC XY: 1 AN XY: 46740

African (AFR) AF: 0.0000400 AC: 1 AN: 25028

American (AMR) AF: 0.00 AC: 0 AN: 8364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2804

East Asian (EAS) AF: 0.00 AC: 0 AN: 2836

South Asian (SAS) AF: 0.000439 AC: 1 AN: 2278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51524

Other (OTH) AF: 0.000768 AC: 1 AN: 1302

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.38	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	D
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.048	D
Polyphen		0.96	D
Vest4		0.49
MVP		0.64
GERP RS		0.45
Varity_R		0.56
gMVP		0.29
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1264284614; hg19: chr1-1362988;